An Atypical Incontinentia Pigmenti Female with Persistent Mucocutaneous Hyperinflammation and Immunodeficiency Caused by a Novel Germline IKBKG Missense Mutation.

While most missense mutations of the IKBKG gene typically result in Ectodermal Dysplasia with Immunodeficiency, there have been rare reported instances of missense mutations of the IKBKG gene causing both Incontinentia Pigmenti (IP) and immunodeficiency in female patients. In this study, we described an atypical IP case in a 19-year-old girl, characterized by hyperpigmented and verrucous skin areas over the entire body. Remarkably, she experienced recurrent red papules whenever she had a feverish upper respiratory tract infection. Immunohistochemical staining unveiled a substantial accumulation of CD68+ macrophages alongside the TNF-α positive cells in the dermis tissue of new pustules, with increased apoptotic basal keratinocytes in the epidermis tissue of these lesions. Starting from the age of 8 years old, the patient suffered from severe and sustained chronic respiratory mucous membrane scar hyperplasia and occluded subglottic lumen. In addition to elevated erythrocyte sedimentation rate values, inflammatory cells were observed in the pathologic lesions of endobronchial biopsies and Bronchoalveolar Lavage Fluid (BALF) smear. Further histological analysis revealed a destructive bronchus epithelium integrity with extensive necrosis. Simultaneously, the patient experienced recurrent incomplete intestinal obstructions and lips contracture. The patient's BALF sample displayed an augmented profile of proinflammatory cytokines and chemokines, suggesting a potential link to systemic hyperinflammation, possibly underlying the pathogenic injuries affecting the subglottic, respiratory, and digestive systems. Furthermore, the patient presented with recurrent pneumonias and multiple warts accompanied by a T+BlowNKlow immunophenotype. Next generation sequencing showed that the patient carried a novel de novo germline heterozygous missense mutation in the IKBKG gene (c. 821T>C, p. L274P), located in the highly conserved CC2 domain. TA-cloning sequencing of patient's cDNA yielded 30 mutant transcripts out of 44 clones. In silico analysis indicated that the hydrogen bond present between Ala270 and Leu274 in the wild-type NEMO was disrupted by the Leu274Pro mutation. However, this mutation did not affect NEMO expression in peripheral blood mononuclear cells (PBMCs). Moreover, patient PBMCs exhibited significantly impaired TNF-α production following Lipopolysaccharide (LPS) stimulation. X-chromosome inactivation in T cells and neutrophils were not severely skewed. Reduced levels of IκBα phosphorylation and degradation in patient's PBMCs were observed. The NF-κB luciferase reporter assay conducted using IKBKG-deficient HEK293T cells revealed a significant reduction in NF-kB activity upon LPS stimulation. These findings adds to the ever-growing knowledge on female IP that might contribute to the better understanding of this challenging disorder.

Microplastics in the Bronchoalveolar Lavage Fluid of Chinese Children: Associations with Age, City Development, and Disease Features.

This study characterized the occurrence patterns of microplastics (MPs) in the bronchoalveolar lavage fluid (BALF) of children with pulmonary diseases. MPs were detected in 89.6% of BALF samples with an average of 4.31 ± 2.77 items/10 mL, supporting the hypothesis that inhalation is a significant pathway of airborne MP exposure to pediatric lungs. Inhaled MPs were predominantly composed of 10 polymer types [e.g., polypropylene (41.9%), polyethylene (19.4%), and polyester (13.6%)], with the majority being smaller than 20 µm. MP levels in BALF exhibited a negative correlation with children's age, probably owing to the preferential crawling and tumbling actions in indoor environments and underdeveloped immune systems of young children. Participants living in urban areas suffered from higher pulmonary MP exposure, likely due to higher environmental levels, compared with suburban/rural residents (P < 0.05). Although no significant differences were found between MP levels in pediatric lungs with community-acquired pneumonia (CAP) and asthma (P > 0.05), the severe CAP group displayed significantly higher MP contamination than the nonsevere group (P < 0.05), indicating that some yet undiscovered relationship(s) between inhaled MPs and pediatric pulmonary diseases may exist.

Juvenile idiopathic arthritis presenting as diffuse alveolar hemorrhage at onset: A case series.

OBJECTIVE: The etiology of diffuse alveolar hemorrhage (DAH) in childhood is often unknown, and it may be an early manifestation of rheumatic disease. Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases in children, but DAH as an onset manifestation of JIA is rare. This study summarizes the clinical characteristics of patients with JIA presenting as DAH. METHODS: We retrospectively analyzed the age of onset, clinical manifestations, imaging features, treatments, and prognosis of five cases of JIA presenting as DAH. RESULTS: Themedian age at DAH onset was 6 months (range, 2 months-3 years). Pallor was the most common manifestation of onset (5/5). Other symptoms included cough (2/5), tachypnea (2/5), hemoptysis (1/5), cyanosis (1/5), and fatigue (1/5). Imaging showed ground-glass opacity (GGO) (5/5), subpleural or intrapulmonary honeycombing (4/5), consolidation (3/5), interlobular septal thickening (2/5), and nodules (1/5). Anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) were positive in five children (5/5), and antinuclear antibody (ANA) was positive in four children (4/5). ANA in three children and ACPA/RF in one child were positive before the onset of joint symptoms. The median age at the onset of joint symptoms was 3 years and 9 months (2 years and 6 months-8 years). Joint symptoms were mainly characterized by joint swelling, pain, and difficulty walking, and the most commonly affected joints were the knees, ankles, and wrists. After the diagnosis of DAH, the five patients were treated with glucocorticoids. Alveolar hemorrhage was effectively controlled in three cases, but the other two patients still had anemia and poor improvements in chest imaging. After joint symptoms, the patients were treated with glucocorticoids combined with diclofenac, disease-modifying antirheumatic drugs, and biological agents. Alveolar hemorrhage was in remission, and joint symptoms were relieved in the five cases. CONCLUSION: DAH can be the first clinical manifestation of JIA, and joint involvement occurs 1-5 years later. Children with DAH who are positive for RF, ACPA, and/or ANA and have GGO accompanied by honeycombing on imaging should be concerned about their joint involvement in future.

Thromboembolic complications of Mycoplasma pneumoniae pneumonia in children.

BACKGROUND: Thromboembolism is less common in children than in adults, but it is frequently associated with Mycoplasma pneumoniae infection in many cases. This study aimed to investigate the clinical characteristics of pediatric M. pneumoniae pneumonia complicated with thromboembolism. METHODS: Hospitalized patients with M. pneumoniae pneumonia complicated by thromboembolism were enrolled from January 2012 to December 2021 in Beijing Children's Hospital, Capital Medical University, China. The data on clinical manifestations, laboratory tests, and treatment were evaluated. RESULTS: A total of 49 cases were enrolled, with a mean age of 7.9 years old, including 27 boys and 22 girls. Consolidation of pulmonary lobe or segment was observed in 95.9% (47/49) of the cases, whereas interstitial change was found only in two patients; 85.7% (42/49) of patients had pleural effusion. Pulmonary vascular thromboembolism was most common in 35 patients, whereas 13 cases had thromboembolism of multiple anatomic sites. The levels of C-reaction protein, lactate dehydrogenase, and erythrocyte sedimentation rate were all increased, with a mean value of 54.08 ± 52.27 g/L, 451.12 ± 218.76 U/L, 43.40 ± 29.43 mm/h, respectively. Blood coagulation test showed that all 49 patients had elevated D-dimer values (median 3.81 ng/ml, range, 0.34-48 ng/ml) and normal PT. aPTT.LA was positive in 74.3% (26/35) of the cases. aCL-IgM was positive in 66.7% (26/39) of the cases. aß2GPI-IgM was positive in 79.4% (27/34) of the cases. The prognosis was generally good in this group. CONCLUSION: Pulmonary arteriovenous thromboembolism is the most common thromboembolism complicated in MPP, and cerebral artery embolism and cardiac thrombosis are common in extrapulmonary thromboembolism. In the cases of MPP with thromboembolic complications, pulmonary consolidation with pleural effusion is the main characteristic. About two thirds of the cases are positive for antiphospholipid antibodies.

Exome sequencing as the first-tier test for pediatric respiratory diseases: A single-center study.

The high clinical and genetic heterogeneity makes it difficult to reach a confirmative diagnosis of suspected pediatric respiratory inherited diseases. Many patients with monogenic respiratory disorders could be missed without genetic testing. We performed a single-center study in Beijing Children's Hospital to demonstrate the clinical utility of exome sequencing (ES) as a first-tier test by evaluating the diagnostic yields of ES for inherited diseases with respiratory symptoms. A total of 107 patients were recruited in this study. We identified 51 pathogenic or likely pathogenic variants in 37 patients by ES (with or without copy number variants sequencing). The overall diagnostic yield was 34.6% (37/107). The most frequent disorders in our cohort were primary immunodeficiency disease (PIDs) (18/37, 48.6%) and primary ciliary dyskinesia (PCD) (9/37, 24.3%). We further reviewed the directive outcomes of genetic testing on the 37 positive cases. Our study demonstrated the effectiveness of ES as a first-tier test in China for diagnosing monogenic diseases of the respiratory system. In the era of precision medicine, ES as a first-tier test can rapidly make a molecular diagnosis and direct the intervention of the positive cases in pediatric respiratory medicine.

Evaluation of Xpert MTB/RIF Ultra Assay for Diagnosis of Childhood Tuberculosis: a Multicenter Accuracy Study.

A multicenter study was performed to evaluate the value of testing gastric aspirate (GA) with Xpert MTB/RIF Ultra assay (Ultra) for childhood tuberculosis (TB) detection in China. In total, 129 children with active TB and 173 children without TB were enrolled. The sensitivity of Ultra in bacteriologically confirmed TB and probable TB cases was 87.5% (42/48) and 44.4% (36/81), respectively. The specificity of Ultra was high (99.4%, 172/173). When Ultra, culture, and acid-fast bacilli outcomes were integrated as a composite reference standard, the percentage of children with definite TB increased from 37.2% (48/129) to 67.4% (87/129). The sensitivity of Ultra is 80.0% (40/50) in children aged <4 years, which is significantly higher than that in older children (48.1%, 38/79) (P < 0.001). Ultra conducted using GA samples can provide faster results, allowing an early and accurate TB diagnosis, especially in younger children with difficulty producing sputum.

Low-dose versus high-dose methylprednisolone for children with severe Mycoplasma pneumoniae pneumonia (MCMP): Study protocol for a randomized controlled trial.

BACKGROUND: Severe Mycoplasma pneumoniae pneumonia (MPP) may develop with long-term pulmonary outcomes despite treatment with macrolides. Combined treatment with glucocorticoids can improve this outcome, though the optimal dosage is unknown. The aim of this study was to investigate the effects of low- and high-dose methylprednisolone in reducing the percentage of long-term pulmonary outcomes for children with severe MPP. METHODS: A randomized, single-blind, parallel-controlled, multicenter clinical trial, methylprednisolone for children with severe M. pneumoniae pneumonia (MCMP), is being conducted in China. Pediatric patients (≤18 years of age, expected number = 402) admitted to the hospital with a clinical diagnosis of severe MPP and fulfilling inclusion and exclusion criteria are randomized (ratio of 1:1) to either a low-dose (2 mg/kg/d) or high-dose (10 mg/kg/d) methylprednisolone treatment group for 3 days followed by tapering of methylprednisolone over 12 days and combined with azithromycin. The primary composite outcome will be incidence of atelectasis, bronchiectasis, or bronchiolitis obliterans at 6-months after treatment. Secondary outcomes include recovery time of patient temperature, proportion of pulmonary lesions absorbed, changes of mucosa identified by bronchoscopy, length of hospital stay, pulmonary function and number of participant(s) needing intensive care. Assessments will be made at baseline, post-treatment and at 1-month, 3-month and 6-month follow-ups. DISCUSSION: This is the first randomized clinical trial designed to evaluate the safety and efficacy of low- versus high-dose methylprednisolone for reducing long-term pulmonary outcomes in pediatric patients with severe MPP. The results of this study will provide scientific evidence to guide clinical practice for the treatment of severe MPP. Trial registration: This study is registered at ClinicalTrials.gov (NCT02303587).